Session Time: 2:30pm-4:00pm
Presentation Time: 3:18pm-3:30pm
Location: Room 208
*Purpose: Obesity is associated with low grade inflammation and bariatric surgery is the only effective treatment in reducing excess weight both pre- and post-transplant.
*Methods: Here, we assessed the effects of obesity and bariatric surgery (sleeve gastrectomies, SGx) on transplant outcome and alloimmune response in a clinically relevant model of diet induced obesity (DIO) and fully mismatched skin transplant mouse model (DBA/2 →C57BL/6).
*Results: Pre-clinical data showed an accelerated graft rejection in obese recipients when compared to lean control animals (p<0.005); notably, bariatric surgery (sleeve gastrectomies) extended graft survival compared to both, DIO and lean mice (p<0.006); bariatric surgery reduced body weight significantly (from 45 g to 30g, p < 0.001) and reversed insulin resistance (glucose level <200mg/dl). Next, we performed a broad metabolomic analysis that indicated restored systemic levels of taurodeoxycholic acid (TDCA) and valine following SGx. When treating DIO mice with TDCA and valine, we observed a dramatic and long-lasting weight loss (30%), ameliorated alloimmune response and prolongation of allograft survival that was comparable to animals that underwent SGx (p=ns). Of note, TDCA/ valine treatment was associated with a reduction of Th1 responses and an increased IL-10 cytokine production (p<0,01); CD4+CD25FOXP3+ T cell frequencies remained unchanged. In addition, TDCA/ valine treatment was associated with a reduction of CD11b+CD11c+ activation in vivo and reduced DC activation and proliferation when cultured in presence of LPS (p<0,001). Next, we tested the effects of TDCA/Valine in metabolic chambers and confirmed that the application of TDCA and valine resulted in a loss of appetite while neither impacting energy expenditure nor oxygen consumption. These findings were supported by a robust decline of the melanin concentrating hormone (MCH), a potent orexigen, in the lateral hypothalamic area in TDCA/valine DIO treated animals (MHC mRNA >4-fold decrease compared to DIO mice, p<0.001).
*Conclusions: Collectively, our study underscores a novel metabolic pathway that may pave the way for a novel therapeutic approach targeting weight loss and alloimmune responses.
To cite this abstract in AMA style:ElKhal A, Quante MMarkus, Heinbokel T, Nian Y, Minami K, Maenosono R, Iske J, Desai B, Banks A, Maratos-Flier E, Elkhal A, Tullius SG. TDCA/Valine Reverse Obesity and Ameliorate Alloimmune Responses through a Decreased Hypothalamic Expression of MCH [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/tdca-valine-reverse-obesity-and-ameliorate-alloimmune-responses-through-a-decreased-hypothalamic-expression-of-mch/. Accessed July 16, 2019.
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